#397 ‒ Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, and emerging treatments | Renato Tomioka, M.D., Ph.D.

25:31Peter Attia:Yeah. Okay. Probably not severity, but yeah, clinical implications, right? Okay. Okay, so the woman with, you said 10 % of women with endometriosis could be asymptomatic or their only presentation could be infertility. So that would suggest that when we start talking about infertility, one thing that should be in the differential diagnosis is untreated endometriosis. But otherwise, most women are going to experience some pain with something, pain with intercourse, pain with her cycle, urination, everything. Then on adenomyosis, what percentage of those are asymptomatic? I don't have the number in my head, but I would say that probably one third, because it depends on the phenotype and the intensity of the disease.

26:18So if you just have one leocyst, myometrial cyst, which is a presentation of adenomyosis, probably these patients, they don't have any symptoms at all. But if you have like a very diffuse adenomyosis or even an adenomyoma, which is a nodule of endometriosis, they bleed out. It's very painful, especially the period is very painful.

26:45Peter Attia:And again, it might sound like a dumb question. What is causing the actual pain? Great question. Great question. Actually, we have three types of pain in endometriosis, Peter. I think that's the most complicated part for us gynecologists to understand because we're not trained for that. But there's the so-called nociceptive pain, pain from the lesion directly, so it just hurts. And here, surgery and treatment, hormonal treatment can help. Second layer is the so-called nociplastic pain, where the nerves are infiltrated by the lesions, and they can have burning sensations, you know, sometimes on their legs, on the back.

27:37And here, medications can help, sometimes gabapentin and SNRIs, right? Surgery can remove some of those lesions. We do this technique called nerve sparing. Very difficult, sometimes impossible to do, but we can try. And the third layer, and most difficult to treat, is the nociplastic pain, when we have central sensation. So you can have a beautiful surgery, your pelvis is clean, but you can still have pain. It's like, imagine this analogy. Imagine like endometriosis lesion is a burglar. So surgery can remove the burglar. Hormones can lock the door. But once you have this alarm system ringing and ringing, years after years the wiring changed and now even a wind can you know triggers the alarm and even removing without the burglar without you know the the doors are locked but you need to you need a different specialist here we need a physiotherapist a pelvic floor physiotherapist and also a pain specialist to treat those patients and that's why the delay in diagnosis and treatment of endometriosis is one of the main causes of this central sensitization, and it's very important for us to treat, even empirically.

29:08Nowadays, the ACOG just published this March 2026, a new guidance on endometriosis diagnosis, and it allows us to not only diagnose clinically, but treat it. Because if you have just based on clinical symptoms, right? If you have a patient that has pelvic pain, dysmenorrhea, dyspareunia, and so on, you can give her a medication to avoid this disease burden years later.

29:42Peter Attia:What's the typical age of presentation today for endometriosis? I don't think we have a typical presentation anymore. We are seeing endometriosis in teenagers. Look at this data. up to 50 and 75 % of teenagers with pelvic pain, they have endometriosis. Three quarters, they have endometriosis. And what percentage of teenagers have pelvic pain? I'm not sure. Presumably it's like 5 % or a lot of them. Yeah, I think a little bit more. A little bit more, yeah. So we are seeing teenagers presenting with endometriosis and if just normal - Again, going back to the etiology of this, anytime you see an increase in the prevalence of something, you have to assume there's some environmental trigger.

30:29Peter Attia:And it would be hard to explain just the number of periods because if she's a teenager, she's still well below 100. So what else do you think? Do you think there are some health factors? Do you think it's like, so for example, we see more PCOS today, presumably linked to more insulin resistance and lifestyle factors that drive that. Is there anything else that you think could be increasing the prevalence of this? We don't have definitive data here, but probably even microplastics, we have some studies about that. Pollution. Oh, you mentioned pollution, yep. Yeah. Diet, probably this sad diet that you talk.

31:09Poor sleep, because remember, poor sleep - The immune system. Yeah, immune system regulation. The macrophages, they just jump from one to the other type, and this may increase the risk of endometriosis. So we are not sure about this question, but... It's probably many things, which is what makes it so complicated.

31:29Peter Attia:Yes. So the implication, of course, of what you just said with the burglar analogy is you need to treat as soon as possible because the longer you wait, the more you rewire in a negative fashion. so let's talk about treatment options for well let's actually talk more about the diagnosis let's go down the formal so a woman presents to you or to a gynecologist and with a story and actually how uniform is the understanding of this amongst primary care doctors and gynecologists or is everybody attuned to making the diagnosis based on a presentation or do women slip through the cracks? Oh yeah, unfortunately not.

32:12Because if you look like the diagnosis, the lapier is five to 12 years, depending on the country. I believe in the US is around six years. And in Brazil? Brazil around seven years. So from the first symptom up to the diagnosis,

32:31Peter Attia:can you imagine like five up to 10 years? No, I can't understand that. So that means that for a period of five years, a woman is saying to somebody, I'm having symptom X, Y, and Z, and they're not able to make the diagnosis? Mainly because of, I think, three factors here. The first one is this cultural normalization of pain, right? Female pain, especially. So they are told that, oh, that's normal. Just have a medication, have an anti-inflammatory and go. But some teenagers, they just can't go to school. They miss school. Sometimes they miss work. They cannot properly work. So we have the estimate cost is around$80 to$120 billion per year.

33:20And two-thirds of that is productivity loss, not only medications and hospitalizations and surgeries. So that means that we have this big culture, unfortunately, of normalization, right? And misleading. The second one is that we don't have a biomarker, like a simple biomarker, like a blood biomarker, right? We need a very good imaging system that's actually very simple, not that complex, like a transvaginal ultrasound, but with a specialist or even an MRI. And yeah, I think that's, and the third one would be that traditionally the diagnosis has been made with diagnostic laparoscopy, right? Which is a big step to take.

34:04Yeah, we shouldn't do that anymore. Okay.

34:07Peter Attia:So let's talk a little bit about that. So for folks unfamiliar with the term diagnostic laparoscopy, laparoscopy of course is when you put actual cameras and air, insufflate the abdomen, put cameras inside, and this is a surgical procedure. It requires general anesthesia. And I guess the rationale for doing that was we are looking for endometrial tissue inside the abdomen. So that's as good a place to look as any. And it's easier to look with your eyes, which is what you're able to do with a camera in an insufflated abdomen than it is to look with a CT scan. But now you mentioned MRI and then obviously ultrasound.

34:49Peter Attia:So when did the shift of diagnostic acumen or success start to move towards non-invasive or non-surgical treatment? That's a good point. Around 25 years ago. Okay. So for us in Brazil, the specialized ultrasonography is a very good exam. We have Dr. Luciano Achamia, who's now in Boston, the Mass General. Manuel Orlando, they are like one of the best radiologists in the world for endometriosis. and they developed this protocol in which you have bowel prep. Just like a colonoscopy or a sigmoidoscopy? Yeah, much more like simple. Okay. You have this enema like one hour before the exam and no residue diet.

35:43But that simple protocol with gel inside a vagina so you can look into small lesions and the bowel, bladder, and you can even see the layers of the bowel. So it's a beautiful exam. But that started around 25 years ago. And that's not widespread yet. I know that I was just talking to Luciana today, and she told me that I think in Mayo Clinic, Arizona, there's one doctor doing that, Scott Young, but not for everybody. I think in the U.S. mainly is MRI. Right. My MRI and ultrasonography, they have very high sensitivity, about 95%, 98%, and very high specificity too. But for superficial lesions, just let me step back.

36:37We have three phenotypes, right? The superficial lesions, the deep infiltrative endometriosis, and the endometriomas, the cysts of endometriosis. So for those superficial lesions, ultrasound, sometimes it misses -

36:53Peter Attia:You say superficial, you mean superficial away from the endometrium closer to the peritoneum? Actually, peritoneum, but the definition will be - Not deep within the peritoneum, just sitting right on top. On top of the peritoneum, yeah, but less than five millimeters. Okay. And so just to orient everybody, because the anatomy here is actually a little confusing, This means imagine you could go inside a woman's abdomen and what do you see? Well, you see nothing because it's all collapsed. But so let's assume you can put air into there and blow it up and separate everything. You have bowel surrounded by peritoneum.

37:29Peter Attia:You have the kidneys behind the blood vessels, et cetera. It's basically just a potential space. And what would be, and by the way, included on top of that peritoneum, you would see the uterus, you would see the ovaries. fallopian tubes the fallopian tubes between them the ligaments and is the most common place you're going to see these endometrial deposits situated on top of uterus fallopian tubes and ovaries right behind it ah yeah right behind the uterus uh the lig the ligaments like the so-called utero sacral ligaments because just of the anatomy and gravity you know most lesions they just stay there.

38:15But sometimes they can travel.

38:17Peter Attia:Yeah, you said it could get up to the diaphragm. So that's a big transit. Yeah, 80 % on the right side because of the anatomy of the sigmoid. So it blocks the left side mainly. But yeah, the bladder, around 10 to 12 % of endometriosis patients, they might have urinary tract lesions. But mostly it's on the pertineo. And then what That's rare. Because the space is too tight. So it needs to go inside from the uterus, sacral ligaments, from behind the uterus and go to the septum. So that's rare, but that's very hard to treat because sometimes it goes deep into the muscle floor of the pelvis and invades the nerves.

39:08And those patients present with lots of fibrosis. Okay. So if you're doing an ultrasound, how is this different from any normal transvaginal

39:18Peter Attia:ultrasound? Is the difference that you're doing the enema and the bowel prep so you can get a better look posterior? Very important question, Peter. If you do a normal ultrasound and you don't have endometriosis in the report, it doesn't mean that you don't have endometriosis. That's one of the most important things, I think, in this episode. So if you complain about pain, you have dysmenorrhea, dyspareunia, and so on, and you do a normal ultrasound, that's one of the problems. That's very, very low sensitivity. Very low sensitivity. Yeah. We see that a lot. But we have three layers of ultrasound.

40:01This is the normal one, the regular, the augmented ultrasound with the sliding sign, So you can use the probe to push the posterior wall of the vagina and see if there is any adhesion there. So, and sometimes we, even without bowel prep, it's better than the normal ultrasound. But the best will be for the detailed protocol with an expert with this bowel prep to look into the pelvis.

40:32Peter Attia:And who does this, a radiologist or the gynecologist? A radiologist. Sometimes it's a gynecologist specialized in radiology. And again, just because I've never done any of these procedures, so it's not clear to me what the difference is. So a regular transvaginal ultrasound, I assume is a relatively small device, like the size of a pen? No, a little larger. How big in diameter? Would be something close to this arm here. Okay. So basically an inch in diameter, two centimeters in diameter. Okay. And you mentioned that the second thing you want to be able to do is push the probe into the posterior or the furthest part of the uterus.

41:11Peter Attia:Now, are you doing that because you're trying to get the probe to look further or are you trying to elicit pain? Yeah, to move the uterus. Okay. So you can see this sliding sign, right? Okay. And MRI cannot do that, right? Right, it's static. It's static, yeah. And the probe can see 180 degrees plus in front? Yeah. Okay. So then when you're, and again, I'm still a bit unclear as to why the bowel prep is needed. So you can check for endometriosis in the bowel, especially in the rectum. I see. And if you have stool in the rectum, you can't get, you need air on the other side. Yeah. Okay. Or liquid.

41:53Yeah, we need liquid. Okay. Air is not good for ultrasound. Yep, yep. Okay, so is this a different device? Is the ultrasound a different type of device? Good question, no. Actually, the difference is just the experience and the protocol, but it takes time, right? And what is the official name of the protocol? It's called a detailed protocol for endometriosis with bowel prep. It depends on the country. Okay, so if someone's listening to this now

42:21Peter Attia:and they want to do this, It sounds like you've already mentioned Mass General Mayo in Arizona. Is it possible that there's someone who lives in a city where there's nobody that does this? In the U.S.? Definitely. I was talking to my friend, and she told me that in the U.S. This is the woman at MGH. Yeah. Yeah. One of the best. Yeah. And in the U.S. it's mainly MRI. But they do the augmented ultrasonography. Okay. So you can do that, the second layer. but just a few clinics in the u.s probably mayo clinic cleveland clinic they are doing the the protocol for endometriosis and why is that because it takes lots of time like one hour exam yeah so you need to allocate the person and also you need of course the the machine is not available like all the time right so we because we in this country obviously have so many mri machines it's it's easier to do that.

43:19Peter Attia:It sounds to me like the MRI is very good, high sensitivity, high specificity. The drawback is you don't get the dynamic phase. But you don't, yeah, but it's not that good for bowel endometriosis. And is it a safe assumption that a woman who's having pain with stool is more likely to have bowel endometriosis? Definitely. So then if you have a woman who is suspected of having endometriosis, but has none of the rectal symptoms, are you more confident that the MRI is going to make the diagnosis? Yeah. Probably sufficient. Okay. But if you are planning a surgery, the ultrasound is, for me, is essential.

44:00Peter Attia:You would never operate without the ultrasound. Yeah. We have the privilege in Sao Paulo to have access to probably five or six very good radiologists that do this type of protocol. You have five or six people in one city that can do Yeah, St. Pauli is one of the best cities to do, probably the best city. Italy is also a good country for that, but it depends on people, right? Yeah. So Manuel Orlando, Luciana Chamier, Ana Luisa Nicola, there are a few radiologists that are very experienced, not only in diagnosing, but also the follow-up of those patients. So, for instance, Luciana, she used to not only do the ultrasound, sound, but then she would go inside the OR with the surgeon to look.

44:44To correlate what she, I mean, that's brilliance.

44:47Peter Attia:Brilliant. Yeah, that's the brilliance. But that's very rare, unfortunately. So you made a very interesting point, which is you can make the diagnosis with MRI with one blind spot, which is rectal. Now let's talk about treatment. So... I would just, sorry to interrupt you, Peter, just to be clear. MRIs is better for extra pelvic lesions, such as diaphragm, and for the lateral part of the pelvis. Where the ultrasound loses its echogenicity. Yes. So, for instance, to see the ureter and to look for the deep pelvis, the nerve infiltration, it's better than the ultrasound. So do you do both? Sometimes.

45:35Mostly both. Yeah.

45:37Peter Attia:And what's the sequence of MRI, by the way? Is it special? Does it require gadolinium? No. So non-contrast? No contrast. T1, T2? They just usually put some gel inside a vagina. T1, T2, that's it. Okay. So relatively easy MRI. Yeah. Probably a 20-minute scan. Yeah, but there are some pitfalls, like movements, you know, bowel movements. Yep. The patient cannot stand too much, you know. Sometimes you just get some artifacts. Yep. Okay. So now let's assume you have the diagnosis. What are the treatment options? How do you think about non-surgical and surgical treatment options? So it depends a lot on the object, right?

46:21If the patient is trying to conceive, we have another section. If she's trying just to get a better life without pain and not wanting to conceive now, we have much more options.

46:34Peter Attia:Okay, so let's start with that. Let's start with 20-year-old woman not trying to conceive, but having pain and just wants symptom resolution, but wants to preserve the option of conception in five years. So we have a list of questions. First one is, do you want to get pregnant in the future? How many children do you want? It's hard to answer that if you are 20. how is your ovarian reserve amh enterofallical count very important disease phenotype what i mean here do you have endometrioma the cyst because this is a very special phenotype which can lead to lower ovarian reserve and also the surgery can impair the enterofallical count and even the AMH.

47:24And how's the pain? If she's presenting with pain, we mainly start with a pill, like a birth control pill, because those patients, they usually are not trying to conceive, so they want contraception, right? And if the patient doesn't have endometrioma, we can use an IUD, like a Mirena or a Chilina.

47:48Peter Attia:In addition to an oral contraceptive? No, just, just we we tend to use just one okay so mirena is not good for cysts because it doesn't suppress the ovulation right so but if the patient has like no endometrioma you can use either a mirena benefit is like five years of treatment and a mirena is progesterone coated why would you use a mirena over any iud because you need the progesterone action you're trying to suppress endometrial hyperplasia. That's it. And to avoid menstruation. Okay. Yeah, so in other words, a regular IUD doesn't necessarily suppress, whereas a Mirena will. It's just an inflammatory event for conception.

48:34It prevents conception, yeah.

48:35Peter Attia:Okay, and do you... All things equal in this example I gave you. So 20-year-old woman who wants to preserve her right to fertility, but at the moment is just trying to deal with pain. she has pelvic symptoms how are you deciding between the Mirena and the oral contraceptive that's a good question if she doesn't have myofascial pain which is like a contractions in the muscle part of the pelvis and Mirena is a good option so no endometrioma no myofascial pain Mirena is a good option but sometimes they just don't want to insert Mirena right so you can start with a pill, a progestin-only pill, like norethindrone or dianagest or desogestrel, or you can use a combined contraceptive pill, like the traditional ones, right?

49:27Peter Attia:Estrogen, progesterone. Yeah, ethinyl estradiol or just estradiol plus progestin. And you don't use a low dose? You don't use a low loestin or you do... Yes, we prefer using a low dose. The lowest effective dose. Yeah, because remember, estrogen can activate the lesions, so it's better to use the low dose. But the data points to, like, they are pretty much similar. So if we do that three months or six months later, the patient is not better. We can change the method or we can plan surgery. But mainly we try to use medications. And why is that? because if you do surgery right from the beginning it's very probable that this patient is gonna recur endometriosis like in five years or even 10 years and she'll need more surgeries afterwards and the surgery here is a laparoscopic procedure it's a blunt force tool you're going in and you're literally laparoscopically cutting out excising and you're and are they that visible to the eye Yeah.

50:38Most of lesions, they are visible, but there are some tiny lesions that we cannot see. And that's why probably the recurrence rate, it's not actually recurrence.

50:47Peter Attia:Think about how different this is from cancer, right? Like endometriosis presents like metastatic peritoneal cancer and no one in, there's no treatment that would ever involve surgery for that. You treat this systemically. Once the cancer is at that level, it's only systemic treatment. and and the reason of course in part is because you can never get it all even you if you only took what you can see you know you're missing things that are below the threshold of your vision and so is that not the case here or is it the case that you're you're missing things and that when you say the problem with surgery is she's going to recur in five years is it that she recurred in five years or it's she's just going to present with what you didn't see yeah That's the point.

51:34Yeah. Sometimes even with a good surgery, excising all the lesions, if you don't use a medication after surgery, recurrence rate is around 10 % per year, especially in endometriomas.

51:49Peter Attia:So it might be that surgery doesn't cause recurrence. It's just that surgery is a sign of recalcitrant disease. that it's disease that doesn't respond to medication. That's it. And that's why those patients need repeated surgery. And that's where the progesterone resistance come in. And do you have an assay to measure this or is it, it's just a clinical diagnosis? We don't have it. Yeah, we don't have it. And remember, they produce aromatase, they produce their own estrogen, like their own fuel to keep growing. So we don't have like a chemo for endometriosis. we just have this ovulator blockage you know we just suppress ovulation and by doing that we of course we decrease the risk of recurrence there's a study published that showed that if you insert a Mirena after a surgery recurrence rate is 88 percent lower to placebo so it's better to use something after surgery.

52:54So coming back to that patient with the patient 20 years old, probably she's going to respond to medication. If not, we can change the medication or we can plan surgery. But always, we should think about this as a chronic disease. And there's this concept that was published in Nature Reviews seven years ago by Charles Chapprón, a French group, that calls the endometriosis life. life. What that means that we should not only treat the, like the main symptom, but we should think about the life of this patient that has this disease that is chronic, like type two diabetes, type one diabetes and so on.

53:36But we are mainly doing just one appointment, one surgery or one medication and go. We're not thinking about the life, like what's going to be like in five, 10 years, right? So we should change the mindset on that. Okay.

53:54Peter Attia:Let's now consider a woman who's in her late thirties. She's had two kids. AMH is declining. So she's technically still fertile, but is not trying to conceive again and is mostly just trying to deal with her symptoms. And she has significant lesions in her pelvis. How do you approach her? So first line, medical therapy. Because remember, if she doesn't want to conceive, she needs contraception. So we could use a combined pill or progestin. In Brazil, we have this dianogest, which is a very good progestin for endometriosis. In the US, we have the natiza. Natiza is like estrogen, estradiol plus dianogest.

54:43but you need to use only the active with Dianogest. There are 22 pills inside a box. And if she responds well, that's it. We are controlling the disease, right? And if not, you go to surgery. Or we can use a Mirena.

55:01Peter Attia:Okay. So now let's go same question, 36-year-old. Everything I said is the same, except now she wants to conceive, but her AMH is, as I said, declining, and therefore the clock is running out. So probably the objective is have a baby, right? Yes, she wants a baby. It's not just controlling pain. That's right. But sometimes they present with both, pain plus infertility. So this patient, we have a series of questions that, remember, infertility is a couple's disease. Probably the only disease that I know in medicine that involves two people. It's defined by the incapacity to achieve pregnancy after one year of trying to do that.

55:43So you need to investigate the male factor, like a sperm analysis, and you need to investigate other factors that not only endometriosis can impair infertility, right? So you need to ask, request a karyotype and some other exams like a hysterosopengogram.

56:03Peter Attia:So let's say you do the fertility workup and you do not see any evidence in the mail for, uh, with motility count or anything like that. And I'm making this up because I don't know if this is how it would present. They don't seem to have difficulty with a chemical pregnancy, but it never, she's always miscarrying at four weeks, six weeks, eight weeks. She's never getting past. Is that consistent more with maternal age? Yes. Okay. So how does the infertility of endometriosis present structurally? They can't implant. Very good question. Actually, now we mainly think of the mechanism about a mechanical mechanism.

56:55We think that it's mainly mechanical not biological okay so the tubes are compromised so they can't pick up the oocytes or they can't permit the fertilization inside the tube and transport the embryo back into the universe right and surgery can fix that sometimes if the tubes are not too damaged but we have some adhesions not too much but you know you can can do that by laparoscopy or robotic surgery but it depends a lot on the couple. If male factor is okay, if age is okay and the couple just want like one child, probably this 36-year-old woman, she has time to do that. And if she doesn't get pregnant after one year of surgery, you can go -

57:54Peter Attia:where you attempt to remove any at all adhesions, and just doing that, the hope is that the fallopian tubes become less dysfunctional. You can restore the anatomy and the functionality of the pelvis. And is that because it is such a mechanical issue where the adhesions can literally kink the fallopian tubes or create obstructions? Yeah, primarily yes. But of course, we have plenty of data showing that we have molecular differences between endometriosis and non-endometriosis pelvis. For instance, we have C-reactive protein, IL-6, TNF-alpha. But clinically, it's mainly an anatomical problem, right?

58:34Peter Attia:This is, it's so hard to believe that it's that crude, if you will, that it's plumbing, basically. Yeah, but there are some authors that may argue that implantation, so the eutopic endometrium is also dysfunctional molecularly. But clinically, not that much. Why is that? Because we have beautiful data and papers published like 20 years ago that compared women without endometriosis, donor or all sides, so good quality embryos, and they transferred the embryos, the implantation rate, miscarriage rate, and live birth rate were pretty much similar. So, which means that clinically, endometriosis probably doesn't impair implantation.

59:23And that's very important for IVF too, because if you have a frozen embryo, you do IVF and you freeze all the embryos. If the patient has endometriosis, does she benefit from surgery before doing the frozen embryo transfer? Probably not. But if she has adenomyosis, she will probably benefit from doing the hormonal suppression. because you cannot operate on adenomyosis, mainly just the adenomyomas. They are not that common. But we cannot treat the uterus with a laparoscopy.

1:00:02Peter Attia:So in other words, the only women who can be relieved surgically from adenomyosis are women who no longer want to conceive because you're going to do a hysterectomy. Do you do the oophorectomy as well? Depends on her age and over and reserve. but we always do the self-injectory. You always take the tubes out when you take the uterus now. Yeah. Great, yeah. Is that standard of care? Oh, yeah. There's no gynecologist that would ever leave tubes. Yeah, because we know. Okay, you know that that's what it is. Yeah, they shouldn't, yeah. Okay. So I didn't understand something you said a minute ago. You said that when you took a donor egg, a healthy, young, perfect donor egg, chromosomally normal, morphologically perfect embryo, and you transferred it, it had the same rate of failure as the woman with endometriosis's own egg, correct?

1:00:56Peter Attia:No. If you are looking just for recipients of donor eggs, one group has endometriosis, the other one has no endometriosis, confirmed by laparoscopy, which is very important, because mainly those studies, they are very heterogeneous. And they mix and they just don't know if the patient has adenomyosis too. So my opinion is that the missing factor is adenomyosis. This can confound implantation rate and miscarriage rate. So what I'm saying is that if you transfer a good embryo in the uterus of a patient with or without endometriosis, we have pretty much same results. Ah, okay. You understand that?

1:01:46Yep. But if a patient with endometriosis is doing IVF, she will probably have less oocytes, less mature oocytes, and less embryos to transfer, which means that she needs much more cycles to do than the patient without endometriosis. But that doesn't mean that the quality is impaired. It's very subtle. We have also molecular data showing that all sites in patients with endometriosis, they are not normal. But clinically, if you look into the data, just ask, I've had patients with endometriosis or without endometriosis, is there any difference in quality? Probably not. Okay.

1:02:40Peter Attia:Even any play rates, they are similar. Because you're matching for age. That's it. Yeah. Age is the proxy for a chromosome of neurologis. Yeah. Okay. So in the case of this woman who's in her late thirties, are you going to treat her surgically and give her a year? Are you going to harvest eggs to give her a year? Like what is your algorithm? So probably we're going to offer both options, but IVF is the way to go here. Because up to 34, the difference in between a blastocyst with 31 or 34 years old, like in a patient that is 31 or 34, is not that different. It's about 35 % of aneuploidy about that.

1:03:37If you are 30.

1:03:38Peter Attia:Is it that high? Yeah. A 31 year old woman has a 35 % chance of aneuploidy? 30 to 35. Almost one third of blastocysts, they are aneuploidy. I mean, I just don't think of 31 as old. Yeah, I know. I think I almost think of that as prime reproductive age. Yeah, prime time would be like 25 up to 30. Because it's very interesting. So it falls off very quickly at 30. especially after 35 and 35 and you ploidy is is around 40 around 40 and 38 around 60 40 around 70 percent 42 around 80 85 percent so it ramps up and uh so that's very important so if you draw i want to make sure you and i are talking about this very casually but i want to make sure the listener understands what we mean.

1:04:35Peter Attia:Aneploidy is when the egg is split and you don't get an equal number of chromosomes. So you get either two or zero instead of the one chromosome you want. And that's almost uniformly fatal. Those almost always result in miscarriages. There are a few notable exceptions like trisomy, you know, Down syndrome, which is what? Trisomy 21? Yeah. So the definition is like aneuploidy is an abnormality in the number of chromosomes so we have 46 xx a female or xy a male but so the normal way would be like 33 chromosomes from the egg x and 33 from the sperm, X or Y, right? So if you do the math, it would be 46.

1:05:2723 and 23. Yeah, 23. Sorry, yeah, 23 and 23. Yeah, so 36 in the end. But if you have problems in the egg, because essentially any employee, they come from the maternal side. like 93 and 95 percent there they come from the outside due to errors in meiosis so they don't split the chromosomes and now you can get monosomy one less or trisomy as you said they are the most quote unquote dangerous because those babies can live they can have the disease Monosomy is not, we don't have a compatibility with life, just the monosomy of X, which is Turner's. So mainly we're having an implantation failure problem, so infertility, and that's invisible to the exams, right?

1:06:22So a 30-year-old woman with normal exams can get pregnant. Why is that? Because she's 38. Most embryos, they are not normal at that time. and we can have also miscarriage risk here.

1:06:39Peter Attia:Okay, so you're going to pursue both paths in parallel with her, but given her age, you're going to harvest some eggs and have them handy. Yeah, just coming back to the case. So we could do potentially two ways, two routes here. First one would be to go directly to IVF, then freeze all the oocytes or embryos, mainly embryos here. then we can transfer the embryo later on. Between freezing the embryos and transferring, you can perform surgery when, if the patient has large endometriomas, like larger than five to six centimeters, because they can... They can get that big. Yeah. That seems massive.

1:07:25Yeah. I have a patient now, she has 12 centimeters in one side and eight centimeters in the other side.

1:07:32Peter Attia:Is the size proportional to the symptoms? No. No. So it's not, because you tell me that, I would assume this woman can't leave her house. Like that would seem debilitating, but no. Yeah, that's the problem of the classification system that we have. We tend to use the ASRM, that's the American Society for Reproductive Medicine Classification, but it doesn't capture it all because it doesn't match the severity of the disease. It's classified from one to four, like mild, minimal, moderate, and severe disease. But it's just like a map, like a surgical description. It doesn't match with pain, neither fertility.

1:08:13So that's a problem. So ASRM4 would be like very severe disease, but she can be asymptomatic. While a stage one patient could be like at their homes, just having pain. so on right so that's a problem we have but we have like talking about classification and scoring we have this endometriosis fertility index which is a score based in some you know you give like zero to four depending on the quality of the tubes and the fimbres and the ovaries after surgery so you can predict the rates the pregnancy rates after surgery so if the score is high like nine or 10, they have almost 65 % of chances of getting pregnant naturally after surgery.

1:09:04So that's useful, which means that if the tubes are not okay, they are dilated, or you did have to proceed, you need to do a self-injectomy, probably the chances are not that high after surgery, so you can walk them through IVF directly. so just coming back to that patient so if if you freeze the the embryos then you can operate on the endometriosis if there is indication mainly indications are large endometriomas pain the quality of life is not good you can operate on them and small bowel lesions that can obstruct and sometimes ureteral involvement, which can lead to kidney function loss. Actually, I had a patient with, she had a nephrectomy, left nephrectomy, due to endometriosis in the ureter, like silent disease, mostly.

1:10:06Peter Attia:And she developed hydronephrosis? Hydronephrosis, and the urologist performed a nephrectomy. Oh. Yeah. So those are the red flags. Those are the reflex to perform surgery even without symptoms. Yeah. Like appendix is important too because sometimes it just mimics neuroendocrine tumors. Yep. It's essentially the same phenotype. Wow. And small bowel and ureterum, you need to operate on them. Okay. Let's talk about a 32-year-old woman. comes to you, she has had difficulty conceiving, two failed IVF transfers. You're seeing her for the first time. You do a workup. You find she has adenomyosis. What can you do to help this woman?

1:10:58That's very common. A very good example, Peter. So if she still have embryos frozen.

1:11:05Peter Attia:Yes. Let's assume she still has... So she has three embryos still frozen. Two of them... She got a lot. She had a decent reserve, but two have failed. And now they don't want to waste anymore without knowing what's going on. So that's why they came here. So she has embryos that are frozen and you can perform... If she didn't do that yet, a GnRH analog or agonist use before the transfer. What that means? that you can treat adenomyosis with medication, suppressing the ovulation and suppressing the estradiol levels. So it can produce like a menopause symptoms. That's the side effect. But we have data showing that this can increase implantation rate, but decrease miscarriage rate and increase live birth rate.

1:11:56So why does that work? You are treating the uterus, right? So estrogen can trigger adenomyosis lesions. Just like endometriosis. Just like endometriosis. And if you use, generate antagonists, we have now in the US... What are the preferred ones? We prefer, like we have much more data with analogs, the agonists. Lupron, it's called the goceroline. They are injectable subcutaneously, monthly.

1:12:26Peter Attia:So two to four months with this. and then we transfer the embryo using just tiny levels. The smallest amount of estrogen. Yes. And high amounts of progesterone. Okay. So that's the strategy. Nowadays, we have the antagonist, the oral antagonist in the US. They are very expensive. They are called allegolix and relegolix, but they are oral medications. We had just one paper published last year that compared the use of antagonists versus agonists, and they're pretty much the same. Here we have less side effects. They're very expensive. I think around$1 ,000 per month. So in Brazil, we don't have these medications.

1:13:13We mainly use the agonists. And by doing that, we can achieve similar rates of pregnancy and miscarriage as patients if she didn't have anomyosis. Adam meiosis, sorry.

1:13:26Peter Attia:Okay, so you're going to go four months. By the way, it's not clear to me why an agonist and an antagonist both work. Oh, sorry. Do they both produce a lower level of estrogen? So mainly is the initial mechanism, the molecular mechanism in which the agonist can do a call, we call this flare-up effect. So it occupies the receptors and it triggers a flare-up of FSH and LH, and then can lead to ovulation. But after two to four weeks of medication, then you down-regulate the receptor and then you have this suppression, hormone suppression. So you produce the menopause, essentially, chemically. But the antagonist, the action, is right in the first medication.

1:14:13So you don't have this flare-up effect. But essentially, the objective is the same.

1:14:20Peter Attia:So you said about four months of that. And if you were to take an ultrasound of that woman every month, what would you be seeing in her myometrium? How would it be changing? Good question. Not much, but yeah, sometimes we just see the uterus shrinking a little bit, like reducing in volume. But sometimes the lesions, they are there. And why did this woman have a hard time conceiving? You said this is a common presentation. But what is it that in this woman with, and let's assume that this is IVF, so we know that these are good eggs, right? These are chromosomally normal eggs. What prevented the implantation in her?

1:15:01Peter Attia:Actually, it's a problem in pregnancy maintenance. I see. So she implanted, but something happened in the first week or two weeks, or where is she typically failing? Six to eight weeks. Oh, wow. Yeah, sometimes even further. Okay. And why? because there are contractions in that junctional zone. And the uterus is just trying to kind of expel the embryos. And, okay, so then you give her four months of treatment, but you said you don't really shrink the adenomyosis. Morphologically, not that much. But chemically, you change. Chemically, yes. Yeah. And then you can give her the embryo back, low dose of estrogen, lots of progesterone, the embryo implants?

1:15:50Peter Attia:And is there a critical window in which she just needs to make it through to then not have the adenomyosis or any form of contraction be a problem? Does this increase her risk of premature labor if it starts to contract too soon? How does it play out through their nine months of pregnancy? If you do the treatment, you have higher chances of implantation and lower chances of miscarriage, but we don't have data on pregnancy complications. But we know that endometriosis and adenomyosis, they can increase the risk of preterm birth, like preeclampsia and small for gestational age, C-section rates. So if you're speaking to this woman before you'd go through all of this, you would say to her look, if you were a 32 year old with none of these issues, you had no adenomyosis, you had nothing, and we were just doing IVF because there was some reason you were struggling to conceive, your rates of success would be X.

1:16:54Peter Attia:Now, because of this condition, how much less are your chances of success? Around 30 % less with adenomyosis. Wow. But it depends on the phenotype. If you have the involvement of the junctional zone, you have a three times higher risk of miscarriage. Because it's more likely to contract. Yes. It's just right on top of this surface where the embryo is going to implant. And remind me again, did you tell me already why you think adenomyosis is occurring? We think there's a disruption basically in the boundary layer? Yeah, the desidualization, the progesterone resistance, the contractions in the junctional zone, and the urele sometimes, it just, you can see even, yeah, yeah, the hypertrophy, you can see the contraction sometimes in the ultrasound.

1:17:43Peter Attia:Are there drugs in the pipeline that are trying to address the progesterone resistance? No, I'm not going to say no. It seems like that would be an interesting area of study. Yeah. Because if the, for example, we know that insulin resistance is largely mediated by a failure inside the cell when the insulin molecule hits the receptor and it triggers the kinase in the cell. And we have a sense of what that is, and there's even a drug that can target that directly. So it's conceivable that with enough understanding of what happens when the progesterone molecule hits the progesterone receptor inside the cell, what creates the resistance, it seems that that would be one opportunity.

1:18:27Peter Attia:Yeah, probably. But we are now just You're just giving them much more progesterone. If that woman who was 32 had been diagnosed immediately, could she have been treated with high-dose progesterones and other hormonal therapies to have not arrived where she is? Like during pregnancy? No, pre-pregnancy. In other words, could she have been maintained on some sort of birth control routine for three years prior to trying to conceive, and would that have increased her odds? That's the point, Peter. We think that if we diagnose an adolescent or even a young woman earlier, we can avoid 40 % of the lesions or the disease burden.

1:19:15So yeah, probably yes, but we don't have much data on that.

1:19:19Peter Attia:So why don't we have much data given the prevalence of this condition? Because if you look at the economic side, NIH invests 15 times more dollars on diabetes than endometriosis. But an endometriosis patient might cost around$16 ,000 per year, while a diabetic patient would cost$12 ,000 per year. so we don't have much funding for that. Why do you think that is? That's a complicated question. I think that's because we're just recognizing that endometriosis now is an important factor. We're seeing movies and documentaries about that. So I think that's just, it's coming up, you know, that's it. I think that's, it's just a question of time, probably.

1:20:21Like menopause, right? Yeah. That we're seeing this revolution.

1:20:25Peter Attia:Are there any other good case examples you can think of that, well, actually, let me give you one more. So let's take another one where a woman is 30 years old. She would like to conceive, but she's not trying to at the moment but her symptoms are horrific so she has the worst symptoms you've ever seen truly debilitating when you look at the ultrasound and the mri you don't see a very high burden of disease you see a very diffuse disease but nothing big you will always try chemical therapy first you'll always try hormone therapy first and that patient no because she's she's gonna try to concede so we have data showing that if you do that you control the the symptoms but you don't have a cumulative effect after stopping the medication so you are treating the disease while you are using the medications and the medications they are mainly contraceptives by nature right so after you stop the medication you just lost some time you know So that patient probably will benefit from surgery because you can treat the pain and then she can try to conceive naturally.

1:21:44Peter Attia:What is the biggest mistake that happens with respect to surgical intervention? What's the biggest patient selection mistake? I would say that if you have a patient that has central sensitization and you think that this surgery is going to resolve that, that's the biggest mistake. Because surgery doesn't attack that layer of pain, the nociplastic pain. So we need sometimes physiotherapy eight weeks before surgery to prepare the pelvis and then you operate on them. And after surgery, two to four weeks, you can restart the physical therapy. So that would be the optimal approach. The second mistake is to take out all the cysts that you know, that you see, like the endometriomas.

1:22:40Because that can impair fertility by reducing, not fertility per se, but IVF outcomes because you reduced AMH.

1:22:52Peter Attia:because each of those cysts, explain why that's the case. Because they are not actually very defined cysts. They're like pseudo cysts. So when we strip them out, you end up by taking some follicles and all sites that are healthy adjacent to the cysts. So we have data showing that. Wait, you're saying that endometrial cysts are dragging follicles with them? No, they are like very attached to the cortical part of the ovary where the primordial follicles are. So when you take out the cyst, you do a cystectomy, you can reduce AMH by 40%, sometimes 50%. So you don't want to take the cysts out if you're trying to preserve fertility.

1:23:39Yeah, but that's a double-edged sword. Why? because the presence of the cyst decreases the... AMH because it's draining. Yeah. It can decrease the AMH.

1:23:52Peter Attia:So shouldn't you harvest the eggs first? That's it. Okay. Yeah. That's it. And the mechanism is beautiful, explained by this phantom reaction, the same one that we know. And it produces hydroxyl molecules that are very toxic to the DNA. so they ended up having this so-called follicular burnout so patients with endometrioma they might have before surgery a low ovarian reserve and if you operate on them you are just decreasing this now that this lower ovarian reserve so it's i think that's one one big mistake I think maybe the third mistake would be to leave a damaged tube, hydrosalpinx, just to preserve the tubes.

1:24:43But we know that this can reduce the IVF chances by half. So if you have a dilated tube... Because the mechanism is like washing the embryos. They are connected to the uterus.

1:24:59Peter Attia:You're saying even if you implant in the uterus, just having the damaged fallopian tube can decrease the success of that? Yes, by half. By half. So there's - Is that widely known? Yeah, yeah. We have Cochrane review on that. Okay. So we have this mechanical effect and also it's ambiotoxic cytokines. Being secreted down into this. Yeah, we need to take out that too. We need to do a self-injectomy. In your practice, how much time are you spending on endometriosis, inclusive of discussions around fertility? Like how often are you operating for this? Operating? Yes. Like you mean surgery, right? Yes.

1:25:40Probably 20 % of cases.

1:25:42Peter Attia:20 % of your cases are removing endometriosis. Yeah, but I have a fertility clinic, so I have this bias. People tend to come to me to do IVF. Okay, so let's pivot and talk a little bit about that. you have arguably the premier fertility clinic in Sao Paulo in Brazil, and this is a huge clinical interest of yours. What do you think is the most misunderstood thing about fertility that we haven't already discussed? Now, you've already made a very important point, which is it's a disease of two people, not one. But as it pertains to the female side of the equation, you've also shared numbers that are even worse than I imagined with respect to aneuploidy and age.

1:26:29Peter Attia:What else do you think is just not fully realized by a person or a couple out there that are trying to conceive? I want just to emphasize that age is the most important factor. And even doctors don't just, they just don't realize it because sometimes you just see the patient with the doctor trying like they operate on them and they try to conceive naturally at 42 years old so that's a big mistake because you're just feeding this desire of natural pregnancy that it's not that common at that age and the risks are very high so age is probably nobody knows that a lot so what What I do in my clinic during the appointment, I show a table we can put in the show notes of the annual polarity rates by year after year.

1:27:29And it's very interesting to know that it's not a... It's not linear. It's not linear. No, it's exponential. And it's not only explanation, but it's like this. We have a sweet spot. It's a J curve. It's a J curve. Very young patients, they can have monosomy.

1:27:45Peter Attia:Oh, I didn't know that. Yeah. And we see that in other primates. We don't know why, but that's not that risky for the couple, right? Because monosomy, they don't live, right? Yep. But the sweet spot would be around 25. And even at that age - So you're saying at 20, you have a worse chance than you do at 25 because the egg is more likely to be missing a chromosome. Yeah, I would say that the risk of annual plodding is probably higher at 20 than 25. But of course - That's incredible. Yeah, it's incredible. And do you think, I mean, this is a silly theoretical question. Do you think that's because evolution is trying to optimize for 25-year-olds having babies?

1:28:30Peter Attia:Yeah, that's why I think - More than 20-year-olds or 18-year-olds and obviously 30-year-olds. It's really saying, I want this, a 25 year old woman is the perfect fitness to carry, deliver, and raise a child. That's exactly what I think. But we don't, we are not sure yet about that. But that's interesting because. Do we think that that's drifted? Like, do you think 200 years ago, if we could go back in time, do you think it would have been lower? No, I don't think so. Because the mechanisms, they should be the same, right? That's incredible. That's unbelievable. Yeah. So that means that if you are 25 and going to IVF, not all the embryos, they are going to be euploid.

1:29:12About 20 % or 25 % will be euploid. Even at 25?

1:29:19Peter Attia:Yeah. 20 % to 25 % of your eggs are already euploid. So you never are walking around fully euploid. So what I say to my patient speaker is that reproduction in humans, it's very inefficient. So if you think about it, you need one egg. You lose 1 ,000 eggs every month. You ovulate. You make one. You lose 1 ,000. Yeah, you lose 1 ,000 apoptosis, but you just have a cohort of like 10, 15, and of them just one ovulate, and you have millions and thousands of sperm just for one to go inside and produce the embryo. And you need one year to say that it's not working, right? Because infertility is like, it's not just, oh, try this month.

1:30:10If you're not pregnant, you have infertility. No, you need to try much more. That's because our reproduction system, it's not that efficient. If you look into the data of like mouse or rabbits, any palliative rate is very low. They're very efficient at producing good embryos. And that means that when we do IVF, we are just grouping, we're just like making more embryos, but we are not increasing their quality. So if a woman is 40, you sometimes need to do much more cycles.

1:30:54Peter Attia:but all things equal if you take the 40 year old versus the 25 year old once you have euploid eggs are the qualities the same or are there other non-visible changes so for example we know with sperm they're not the same even though chromosomally they appear the same between 25 and 50 we know that genetically they're different and so older fathers are more likely to produce children with more neuropsychiatric, polygenic conditions. But what do we know on the egg side? That's a good point. We have data on that. There's a beautiful table showing that the clinical pregnancy with a euploid embryo at 30, 35, 40, and so on.

1:31:41It's pretty similar. But we know from the lab, if you ask an embryologist, she would say that the embryo is not that quote unquote beautiful, you know, sometimes morphologically they are different. The morphokinetics, they are not similar, but clinically it's not that big difference. Interesting. Yeah.

1:32:05Peter Attia:Would you advise a woman who's listening to this, who's 25 years old, who is in graduate school, business school law school medical school pick your favorite who still has five six seven years ahead of her in really really working hard and does not want to have a child in that period of time maybe she hasn't even met her partner yet but she deep down thinks she wants to have a child but it's possible she's not going to be thinking about it for another 10 years till she's 35 So she's 25. And you're her regular GYN. You're doing your regular sort of exam. She tells you all of this. Would you advise her to freeze eggs right now at 25?

1:32:53Not for all the patients, but I would say that it's reasonable to do an AMH. Check your reserve, right?

1:33:02Peter Attia:But let's say she's normal. She's not ahead of time. She's not behind time. She's just a normal 25-year-old. But thinking about the J curve, right? Which is the difference between being 25, 30 and 35 is significant. And she's not just from an optionality perspective. She's, she can't tell you, I, Hanado, I'm definitely going to do it by 30. In which case maybe you could say, okay, it doesn't change much. Yeah. If she, if she's not, if she's sure that, uh, she, she want, she wants child, children in the future, I would talk to her, but the chances, you know, Look at this statistic, Peter. What do you think is the rate of patients that come back to use their own oocytes, like globally?

1:33:50Peter Attia:All the women who freeze eggs. Yes. You're saying how many of them never come back and touch them? Yes, of 100 women that froze their eggs, how many are coming back to use them? To do something with them. Yeah. 75. Actually, around 10%. What? Yes. 90 % of women who freeze eggs never touch them. Yeah. Or because they - Because they get pregnant, maybe. Yeah, they got pregnant. Okay. And sometimes they just don't want to use that. But the sweet spot would be around 30 something, 32, 35, because the cost effectiveness of doing that is better than at 25. So biologically, of course, it makes sense to freeze earlier, but the chances of the time you spend on it, the cost you spend on it.

1:34:47Peter Attia:Help me understand the costs. And I know it's different in Brazil from in the US, but I assume in Brazil, this is all paid by out of pocket. So I think in the same, in the US, I don't even understand. Yeah. US, I think there are some differences. Some insurance might come. Yeah. But let's just talk about the cash price of doing it in Brazil. So if this 25-year-old came and said, I want to go ahead and do this, what is the cost of harvesting, of doing one harvest cycle? In Brazil, she would spend about$5 ,000. U.S. dollars. U.S. dollars, because our currency is like five to one. Yeah, yeah. Okay, so she spends$5 ,000 U.S.

1:35:26Peter Attia:dollars to do one harvest cycle. And then how much does she spend per year to keep them in storage, safe storage? It's like$150. Okay, so nothing compared to the... Okay, so the big cost is she's going to incur that. And again, I'm just being devil's advocate. My view is if you could afford$5 ,000, why not do it at 25 instead of 30 just because you've capped your downside? Your downside is you're out$5 ,000. Your upside is how many would you expect? How many euploid eggs do you expect to get out of a 25-year-old per cycle? We were talking about blastocysts or embryos in day five to day seven, about 80%, around 75, 80 % of the embryos, they are euploid.

1:36:13Peter Attia:But since this is not embryos, you're not going to be fertilizing these. Yes. You're just getting an egg. Yes. So we have a nomogram. So you don't touch them. No. You just freeze them. The M2 oocyte, the mature oocyte. And you won't know until you fertilize. About 75 % of the oocytes, they are mature. So we freeze just the mature eggs. And we have some calculators to estimate the pregnancy rate, and not only that, but the live birth rate, depending on the age and number of eggs. So at that age, probably if you have like 15 eggs, your chances are higher than 80 % of having at least one baby. Which still seems not that high, but...

1:36:56Yeah, but remember, a fertile couple... But that's all the way to baby, meaning... Yeah, yeah, yeah.

1:37:03Peter Attia:So how many embryos and then each implantation has a rate of fall off, et cetera. Yeah. Okay. So. So biologically, of course, that makes sense. Yeah. Economically, it doesn't. I think that, yeah, that's just economics. Okay. The risk is pretty low. Like the risk of ovarian torsion and bleeding and, you know, infections, it's about 1%. And the main driver of that cost is the medication, the procedure. Is it split about equally? Yeah. Yeah, one-third medication, one-third clinic, and one-third lab. Yeah. What is the median age of women who are coming to you to have eggs frozen, but they're not planning to fertilize?

1:37:49Mine is 37, 38. Yes, very high. Why so high? Why are they coming so late for eggs? because I think that's just a new treatment, kind of new treatment. And because I have bias, as we're in St. Paulo, like, yeah. You're treating the hardest cases. Yeah, probably.

1:38:08Peter Attia:So when a 37-year-old woman comes to you, I assume she's been trying for a while to get pregnant. Because she's 37, she's probably had many aneuploidic miscarriages. So she comes to you and says, look, we can't leave this to chance anymore, you're going to do a cycle, you will typically get how many ocytes in her? So my infertile patient is even older, like 40. Like a social freezing is around 37. So it depends a lot on our ovarian reserve. So if the reserve is like normal for a 40-year-old woman. What's a typical AMH for a 40-year-old? would be around one milligram per ml. And that corresponds to roughly how many eggs left?

1:38:54Depends a lot on the cohort on that cycle, which can be different between the follicular phase and the luteal phase. And that's very important from a practical standpoint because sometimes we check the ovaries, we do the enterofollicle count, that's not fine. We wait and recheck another phase. because it varies a lot. But we would expect around eight eggs, something like this. Okay. And eight eggs at 40 is not sufficient mostly to produce aneuploid embryo. Oh my God.

1:39:34Peter Attia:Because eight eggs, you're going to fertilize them and more than half of them are going to be aneuploid. Yeah. So you might get two. Seven, 80 % of them, yeah. Okay, so you might get one to two euploid to implant. Yeah, we say that it's like a funnel. It's very important for the layperson to understand that. You have the follicles. Each follicle might have one oocyte. Every oocyte has a chance of being matured, 75%. Every matured egg can be fertilized. And on day one, present this pronuclei. We say that it's fine. That's the M2 phase. Yeah, after the M2 phase. And then from day one to day five or day six, which is a blastocyst, around 30 up to 60 % of those day one can develop into a blastocyst.

1:40:29It depends a lot on the sperm quality too, and the lab, of course. And on top of that, you have the antibody rate. It's a big tunnel.

1:40:38Peter Attia:Yeah, so hence the inefficiency. You're just multiplying negative numbers after... You're multiplying so many small numbers together that the outcome is very difficult. So when the patient is freezing her own eggs, it's very important for her to know that the funnel. The funnel is steep. Very important. Because sometimes it's very sad to see a patient that is coming back, like she froze her eggs at 34, and she's coming back at 40, and she had just eight eggs. and now you thaw them and then you produce just one blastocyst and doesn't implant. So that's it. And now she's 40. Yeah. Which again, goes back to my question of why isn't every 25 year old woman who is unclear on her timeline, I guess, you know, it's funny, like, I wonder if in countries where population growth is not high enough.

1:41:36Peter Attia:So if you look at a country where the reproductive rate is below 2.1. And that turns out to be a lot of countries and immigration alone won't solve your demographic problem. You actually need de novo reproduction. This strikes me as a reasonable cost for the government to bear. Yeah. J Japan is facing this right now. Yeah. So Israel, uh, in, in Israel, you can do how many cycles you want. You need to produce your family. Yeah. So I think from a longevity perspective, you're right. You can avoid this disease called infertility, but you can prevent that by freezing oocytes earlier. But I think that's a problem of excess right now.

1:42:26We have the technology.

1:42:28Peter Attia:Okay, now let's talk about something very extreme at the other end of this spectrum. So you now talk about that woman who's 40. She's come back. only to realize that nothing worked. But she still wants to have a baby. So right now, her only option is to use an egg donor, correct? Okay. In which case, she will use the egg of a young woman. She'll use the egg of a 25-year-old woman, likely with her partner's sperm. And that's fine. That's a great treatment, right? That works very, very well. But I have now heard about an emerging technology where that woman who is 40 can use her genetic material with the remainder of the egg from a donor so that she has all of the benefits of the young egg except she gets her genetic material in there.

1:43:29Peter Attia:so that the donor is only providing the scaffolding and she could even use a surrogate. So help me understand that technology. Yeah, that technology is called mitochondrial replacement therapy. So that doesn't solve the problem because the problem is in the nucleus, right? Yeah. So the problem is chromosomal. And we had, I think, two papers published last year in New England Journal of Medicine by a UK group, Newcastle, but 22 patients with mitochondrial disease. Because remember, we have like 20 ,000 up to 25 ,000 genes and 37 genes in the mitochondria, the so-called mitochondrial DNA. And for those very specific cases, they basically took out the pronuclei, from the the parents embryo fertilize after fertilization so they have in day one the pronuclei they take out and they insert in a enucleated oocyte new oocyte that has this new mitochondria that are normal they are supposed to be healthy so this solves just the problem of the cytoplasm the mitochondria ah i see so it is not solving the age problem no got it and this as far as I know, it's not available for infertility, but there are some clinics, I think, in North Cyprus or Greece, and they're selling this as an egg rejuvenation.

1:45:13That's misleading, in my opinion. But you are just trying to replicate. It's like a battery swap for the egg, but you're not changing the engine, right? The engine is the main problem.

1:45:28Peter Attia:So is there currently anything on the horizon for the 40-year-old woman who wants to conceive and would like it to be her genetic material, even though she no longer has eggs? Or if she has any eggs, they're not dividing correctly. I think, yeah, not for that situation, but there's a clinic in the UK that is trying to freeze ovaries, like cortex. Mm-hmm. like long years before menopause, like to prevent or to postpone menopause. Yep. Very interesting idea, but we don't have publications on that. Actually, we have a huge line, like a huge wait list of patients trying to do that. Makes sense, but we don't have data.

1:46:17Peter Attia:Sorry, just to make sure I understand that. So the analogy would be somebody with type 1 diabetes that gets implanted pancreatic or beta cells that secrete insulin. Autologous. Yes, autologous. Is this her own ovarian tissue that was set aside earlier in life? Like at 30s. At 30s. So they do a partial oophorectomy. Yeah. And you can then transplant like 45 when you are 45, and then you can postpone. There is actually like a math behind that. You can postpone menopause like 10, 15 years, sometimes even more. Where do they re-implant? In the same - In the peritoneum. Yeah, peritoneal. Okay. Or you could put in the subcutaneous too.

1:47:03Peter Attia:And so you're not only postponing menopause from a hormone perspective, you're postponing fertility. Yeah. Actually, that's mainly for menopause, like to produce her own. That's just to produce estrogen and progesterone. Yeah. But for all sites, we have data, ovarian cortex freezing. but the better outcomes, they come from egg freezing. And why would this autologous ovarian implantation or transfer be superior to just standard menopausal hormone therapy? That's the question. I just gave a lecture last year about that. So I think because of the cultural thing about menopause, right? about hormone replacement therapy after 2002, July 2002, WHI, right?

1:47:59I think there's just this big misconception about menopause hormone therapy. It's much more, it's much easier to just give estrogen, progesterone, and sometimes testosterone than freezing the ovary and then transplanting and probably getting like premenstrual syndrome, you know, symptoms doing that.

1:48:23Peter Attia:Yeah. But we don't have that. But to your question, probably in the future, we're going to have like stem cells producing new oocytes. We are not there yet. I read an article very recently suggesting that that could be five years away. What's your view on that? Are you optimistic? Not that much. I think more like 10 years. Why? Why so difficult? What has to be done? Explain what it is, first of all. Oh, it's, I think I'm not the right person to answer that, but it's very hard to produce an egg. It's easier to produce a sperm. And we don't know the consequences of that. So we need data after doing fertilization and transferring to see if those babies are healthy, they're still healthy.

1:49:13Peter Attia:And we're doing this in animals right now? Yeah. Which animals? How? I think cattle, probably. And so are they doing this in primates yet? I'm not sure, but probably yes. Okay. So what has to be done is you have to demonstrate that you can take a pluripotent stem cell and somehow turn it into an egg. And that hasn't been done yet. But if you can do that, you have to ensure that that becomes chromosomally and genetically normal in the long event. That has been, there's a publication about that, yeah. That you can make the egg out of a stem cell. Yeah, but we are not sure about the consequences and the clinical benefits of the safety of that.

1:50:00Peter Attia:Has it been done in mice? Yeah. And in mice, because their lifespan is short enough, does it produce a normal phenotype? Yeah. Okay. So that's promising, but not guaranteeing. Yeah. But that's going to be like a game changer for us. Yeah. I think when we do that, we are going to not do any more vitrification, like frozen. We are not freezing eggs anymore. Right. So just imagine that. So you're saying in 10 years, any couple of any age could potentially reproduce. Probably. I don't know if that's safe, if that's going to be safe. If you ask me, you are 30, me and my wife, we are healthy, we don't have any fertility problems, would you do IVF or try naturally?

1:50:57Always start naturally. Why is that?

1:51:00Peter Attia:Well, I mean, that's a bit different. I mean, I think I would say for cost and just, there's no reason to rush. I mean, but, but look, if, if you, if you struggled for a year, we wouldn't hesitate to do IVF, right? But for me, I think we are like IVF is the first baby was born in 78. Yeah. So it's actually a new technology. We can't reproduce everything that we would need to reproduce inside the tubes naturally. There are some epigenetic effects which we can't control, and we don't know what are the consequences. So if the couple has this natural chance, I will try naturally. The stem cell takes it to a whole new level.

1:51:54The problem is, yes, you can count on stem cells. Okay. But wouldn't it be better to use my own oocytes than just froze at 35? Yeah. I don't know. Probably, yes.

1:52:10Peter Attia:Is there anything about IVF that we don't know that worries you? What are the unknown unknowns about IVF? Epigenetics. Yeah. And how do you think that shows up phenotypically? Probably some malformations, some neurological consequences, heart disease. Do we see this in the epidemiology? I mean, so again, people born of IVF are still very young. They're not even 50 yet. Louise Brown is like 40-something, 48. She's 48. Yeah. Yeah. But we see definitely, uh, some signs. We, we're not sure about whether it's, uh, bias, a selection bias. Yeah. That's the hard part is how do you get out? Cause by definition, you're talking older parents.

1:53:05Peter Attia:You're talking about more, you know, affluent access. There's infertility. There's so many confounders and we're never going to do a randomized control trial for IVF. But they are showing that if that same couple that needed IVF and then now they are getting pregnant naturally, because sometimes it happens, right? It's mainly a bias, a selection bias problem, not the technology itself. Yeah, but it's a new technology, right? So what are you most excited about in your field today? Actually, I was very excited about this new guidance from ACOG. Very simple, because probably we're going to avoid complications of endometriosis and adenomyosis, especially in those vulnerable adolescents.

1:53:59And not only treat the disease, but as like statin in longevity, you can modify the disease progression. Early. Earlier. and avoid infertility. And I'm very excited about this. So we should spread this word, right? And there's one molecule called HMI-115. It's a monoclonal antibody that targets the receptor of prolactin. Probably this leads to, it's in phase three trial now, and this leads to less pain and less disease progression, endometriosis, because those lesions can express prolactin receptors. Very interesting. Maybe that's going to be the first biologic treatment for endometriosis, that it's not using hormones.

1:54:59So, like, to your point that, why don't we have, like, medications that target... Target the disease directly. Yeah, yeah. Probably we're getting that soon. And I think the diagnosis, Peter.

1:55:16Peter Attia:Yeah. I think with this widespread ultrasonography and MRI and just the awareness of the disease, we're going to not only diagnose and treat more effectively. Okay. So basically the final and closing thought here should be, if you're listening to this and you're struggling with any symptoms that may be even remotely suggestive of endometriosis or adenomyosis, or your partner is experiencing them, the biggest single win is getting that diagnostic window from six years in the US or seven years in Brazil down to six months. That's it. So you just have to be a bull in a China shop and demand a diagnosis and say, I'm not going to take no for an answer.

1:56:02Peter Attia:I want an MRI. And if necessary, I want an ultrasound done with this correct protocol. That's it. That's it. And we're not going to take no for an answer. We're going to get these diagnoses so we can start the treatment because the earlier you start the treatment, the better the prognosis. And you know, Peter, just to close that the cases that stay with me are not the most complex surgeries, not the difficult IVF cycles. There are those women that cry, not from pain, but during the appointment from relief. They finally have a diagnosis. When I tell them, you know, you are suffering. I know that's real.

1:56:41It has a name. We have a plan for that. And if you listen to this and you have pain and you know you are suffering, please don't don't take like this is normal this is just your regular period please have a second opinion and we have technology for that we have treatment for that and we should do that right

1:57:10Peter Attia:a perfect way to end it Renato thank you very much and I really appreciate you getting this message out great to be here thank you man thank you for listening to this week's episode of The Drive head over to peteratiamd.com forward slash show notes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

1:57:50Peter Attia:No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.